The CureTheProcess Campaign

An ESUN Article

Bruce Shriver, PhD
Editor-in-Chief, ESUN

The Liddy Shriver Sarcoma Initiative is pleased to announce that it has become a partner with the CureTheProcess Campaign. The Campaign is focused on bringing about science-driven public policy that will increase the predictability of the regulatory process for rare disease treatments. Their goal is to give even the rarest diseases access to the accelerated approval process and put orphan treatments on the fast track.

The Campaign was formed by the Kakkis EveryLife Foundation and announced during the Partners in Progress Summit hosted by the National Organization for Rare Disorders (NORD) in Washington, DC in May 2009.The Foundation is built around the personal vision of Dr. Emil Kakkis, MD, PhD.

The Campaign has identified the following goals that need to be reached to create a clear path in the development process:

Establish a new Office of Drug Evaluation for Genetic and Biochemical Diseases, consolidating expertise to ensure safe, effective and timely patient access to needed treatment. Biochemical and genetic disorders require specialized training and experience to best evaluate new therapies. The establishment of a Genetic and Biochemical Office of Drug Evaluation would assure that the appropriate rare disease experts are recruited and integrated with existing expertise at FDA.
Create a new standard for the surrogate and biomarker endpoints used for rare disorders, to allow treatments for these diseases to have full access to the accelerated approval pathway. Due to the rarity of the disorders, the use of direct, relevant surrogate or biomarker endpoints as clinical study endpoints is essentially impossible for some rare disorders because none of these surrogates have been validated or could ever be validated in clinical studies and are therefore unavailable for development use. However, the data show that biochemical markers relevant to biochemical genetic disorders are far better predictors of disease and treatment effect than many of the approvable surrogate markers currently used for drug approvals.
Devise new clinical study design paradigms for rare diseases that properly account for clinical heterogeneity and disease complexity to properly capture treatment effects. While traditional randomized, controlled studies have been used in rare diseases, this design is relatively insensitive to changes in heterogeneous patients and fails to allow the assessment of all types of patients with all types of disease outcomes. A creative effort is needed to develop new paradigms in study design that capture individual benefit in a broad array of patients, utilizing all the clinical data to establish efficacy. The medical science needs to drive the statistical analysis.

The outcomes that are expected from these and related changes in the regulatory path:

A streamlined development path will shorten timelines and reduce the financial risk associated with the development of rare disease therapeutics. The result should be a surge in development activity for even the most rare disorders.
More patients with rare biochemical and genetic disorders will get earlier access to specific, effective treatments.
Certain treatments for rare biochemical or genetic disorders that are now unaddressed because of the difficulty in assessing the clinical outcome, will now be targets of drug development as appropriate surrogate markers are identified.
Investment in early stage biotech companies focused on rare diseases will increase and have a positive impact in local communities and biotechnology jobs.

I encourage you to visit the Campaign's website and share their mantra with others: Accelerating Innovation for Rare Diseases (AIRD). You might also wish to read our letter endorsing the CureTheProcess Campaign.

The Campaign distributed the following Frequently Asked Questions which help people understand its mission and goals.

Q: What is an Orphan Disease?
A: An orphan or rare disease is generally considered to affect fewer than 200,000 affected individuals in the United States. There are more than 7,000 rare disorders that combined affect over 25 million Americans and their families but relatively few have approved therapies, drugs or other treatments. The most complete listing of rare diseases can be found at the Office of Rare Diseases Research.

Q: What is the Orphan Drug Act?
A: The Orphan Drug Act was enacted in 1983, to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the law, companies that develop orphan treatments may sell them without competition for seven years, receive tax credits for clinical trial costs, research grants, assistance in clinical study design, and a waiver of the filing fees normally paid to FDA.

Q: What is Accelerated Approval or Subpart H?
A: In response to the AIDS crisis, in 2002 the FDA enacted Subpart H - Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses. This allows the FDA to grant marketing approval for a new drug product on the basis of clinical trials that establish the product has an effect on a surrogate endpoint or biomarker that is reasonably likely to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.

Q: What is a Biochemical Disease?
A: Historically, biochemical disorders have been called "inborn errors of metabolism." The breadth of these disorders is large but in general the diseases are caused by genetic defects for a metabolic enzyme that transforms one chemical in the body to another, which leads to an accumulation of a specific chemical or enzyme that is toxic or harmful to the body.

Q: What is a Surrogate Endpoint or Biomarker?
A: Surrogate endpoints or biomarkers are biochemical or physical signs you can measure instead of traditional clinical measures, e.g. a disease-related chemical or cell in a person’s blood or urine, liver size, cholesterol, or T-cells counts. AIDS drugs were approved because they increased the level of T-cells in the blood and they knew that people who had more T-cells were healthier.

PROBLEMS WITH DEVELOPING TREATMENT:
Q: Why are treatments still not being developed for many orphan diseases?
A: There are many reasons. Some of the diseases are just too rare for most companies to invest in them. Some of the diseases are complicated, making it hard to do the clinical studies. Some are not developed because the regulatory process that the FDA uses to evaluate the drugs can make it so uncertain and unpredictable it is just too hard, and so the program does not even start.

Q: Why are treatments for orphan diseases not being granted access to the accelerated approval process?
A: Because the diseases are so rare, there is a lack of historical data and a limited amount of data that can be collected. Despite the sound scientific evidence that biomarkers are more effective measures of disease, under current rules a surrogate cannot be approved as an endpoint without more data.

Q: Where does the FDA currently review biochemical diseases therapies?
A: They are reviewed in the gastroenterology division, the people that deal with diarrhea and hepatitis. While they have good physicians there, a specialized unit that focuses on complex biochemical and genetic disorders could allow specialization and better knowledge and experience in the specifics affecting patients with those disorders.

Q: What’s wrong with the current structure of clinical trials?
A: While traditional randomized, controlled studies have been used in rare diseases, this design is relatively insensitive to changes in heterogeneous patients and fails to allow the assessment of all types of patients with all types of disease outcomes. Variable and complex diseases just cannot be studied effectively with the current structure and often make the probability of knowing what the effect is hard to show.